title: Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia.
abstract: Early diagnosis is important in familial hypercholesterolemia (FH), a highly atherogenic condition, but internationally agreed clinical diagnostic criteria are lacking. Genetic testing for low-density lipoprotein (LDL) receptor (LDLR) and apolipoprotein B (APOB) gene defects is the preferable diagnostic method, but the best phenotype indication to proceed with genetic diagnosis has not been established. The aim of this study was to assess the predictive and accuracy values of standard diagnostic criteria for detecting disease-causing mutations in 825 subjects with clinical FH aged > or =14 years from 3 lipid clinics in Spain. All subjects underwent thorough genetic testing for the detection of LDLR and APOB defects using the Lipochip platform. FH-causing mutations were detected in 459 subjects (55.6%). By logistic regression analysis, familial or personal history of tendon xanthoma (TX) and LDL cholesterol were strongly associated with genetic diagnosis (p <0.005, R(2) = 0.41). In subjects without familial or personal histories of TX, the diagnostic criteria for FH of the Make Early Diagnosis to Prevent Early Deaths (MEDPED) project, based on age-specific LDL cholesterol thresholds, showed sensitivity of 72.4%, specificity of 71.1%, and accuracy of 71.6%. LDL cholesterol > or =190 mg/dl in subjects with familial or personal histories of TX and > or =220, > or =225, and > or =235 mg/dl in those without such histories aged <30, 30 to 39, and > or =40 years, respectively, showed sensitivity of 91.1%, specificity of 71.1%, and accuracy of 74.2% for a positive genetic diagnosis. This new set of diagnostic criteria for FH was validated in an independent group of 440 subjects from 6 additional Spanish lipid clinics. In conclusion, TX and age-adjusted LDL cholesterol cut-off values have the highest value for clinical diagnosis and indication of genetic testing in FH.
authors.affiliation: Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. civeira@unizar.es
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Jarauta
authors.forename: Nuria
authors.initials: N
authors.lastname: Plana
authors.forename: Daniel
authors.initials: D
authors.lastname: Zambon
authors.forename: Jose
authors.initials: J
authors.lastname: Puzo
authors.forename: Juan P
authors.initials: JP
authors.lastname: Martinez de Esteban
authors.forename: Juan
authors.initials: J
authors.lastname: Ferrando
authors.forename: Sergio
authors.initials: S
authors.lastname: Zabala
authors.forename: Fatima
authors.initials: F
authors.lastname: Almagro
authors.forename: Jose A
authors.initials: JA
authors.lastname: Gimeno
authors.forename: Luis
authors.initials: L
authors.lastname: Masana
authors.forename: Miguel
authors.initials: M
authors.lastname: Pocovi
mesh_terms: D000293:Adolescent; D000328:Adult; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D011973:Receptors, LDL / Q000097:blood*; D018110:Receptors, Lipoprotein / Q000097:blood*; D012680:Sensitivity and Specificity; D013030:Spain
chemical_list: D008078:Cholesterol, LDL; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; C098070:lipoprotein A receptor